The current state of biomarkers of mild traumatic brain injury

Kim, Hanjun; Tsao, Jack W.; Stanfill, Ansley Grimes

doi:10.1172/jci.insight.97105

Cited by 91 publications

(86 citation statements)

References 104 publications

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“…A previously compromised BBB may be more susceptible to an acute inflammatory challenge, where systemic inflammation may lead to endothelial activation, leakiness of the blood-CSF barrier, and astrocyte activation. 18,19 We therefore quantified GFAP in the serum and CSF (Fig 3C). Acute-phase CSF was obtained in 16 of 19 (84%) subjects with acute neurotoxicity (median 8 days, range 6-16 days after CAR-T cell infusion), but only 2 of 24 (8%) subjects without neurotoxicity (on days 6 and 7 after CAR-T cell infusion).…”

Section: Chronic Neuropathology After Car-t Cell-related Acute Brain mentioning

confidence: 99%

“…CSF protein and white blood cell counts returned to baseline levels on day 21. GFAP has been well validated as a marker of astroglial injury in multiple neurological pathologies such as dementia and stroke. 18,19 We therefore quantified GFAP in the serum and CSF ( Fig 3C). CSF GFAP levels before treatment were similar in patients with (median, 5,012pg/ml; range, 1,890-13,028) and without neurotoxicity (median, 5,798pg/ml; range, 1,005-12,366; p = 0.92).…”

Section: Clinical Risk Factors For Neurotoxicitymentioning

confidence: 99%

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Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

Gust

Finney

Li³

et al. 2019

Annals of Neurology

130

178

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Objective: To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. Methods: We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). Results: Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calciumbinding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. Interpretation: Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury.

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Section: Chronic Neuropathology After Car-t Cell-related Acute Brain mentioning

confidence: 99%

Section: Clinical Risk Factors For Neurotoxicitymentioning

confidence: 99%

Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

Gust

Finney

Li³

et al. 2019

Annals of Neurology

130

178

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“…Additionally, long-term consequences of mTBI and PTSD may predispose these vulnerable patient populations to the risk of developing neurodegenerative diseases later in life (Perry et al, 2016;Wilson et al, 2017;He et al, 2019) and are known to lead to worse outcomes when comorbid with other disorders (Lippa et al, 2015;Ahmadian et al, 2019). In that regard, several studies have focused on examining blood amyloid-β (Aβ), neurofilaments and tau levels in individuals with TBI (Bogoslovsky et al, 2017;Kim et al, 2018). Among these, elevated blood Aβ40 and Aβ42 fragments have been detected acutely and chronically after mTBI (Lejbman et al, 2016;Bogoslovsky et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

et al. 2020

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The differential diagnosis between mild Traumatic Brain Injury (mTBI) sequelae and Post-Traumatic Stress Disorder (PTSD) is challenging due to their symptomatic overlap and co-morbidity. As such, there is a need to develop biomarkers which can help with differential diagnosis of these two conditions. Studies from our group and others suggest that blood and brain lipids are chronically altered in both mTBI and PTSD. Therefore, examining blood lipids presents a minimally invasive and cost-effective approach to identify promising biomarkers of these conditions. Using liquid chromatography-mass spectrometry (LC-MS) we examined hundreds of lipid species in the blood of healthy active duty soldiers (n = 52) and soldiers with mTBI (n = 21), PTSD (n = 34) as well as co-morbid mTBI and PTSD (n = 13) to test whether lipid levels were differentially altered with each. We also examined if the apolipoprotein E (APOE) ε4 allele can affect the association between diagnosis and peripheral lipid levels in this cohort. We show that several lipid classes are altered with diagnosis and that there is an interaction between diagnosis and the ε4 carrier status on these lipids. Indeed, total lipid levels as well as both the degree of unsaturation and chain lengths are differentially altered with diagnosis and ε4 status, specifically long chain unsaturated triglycerides (TG) and both saturated and mono-unsaturated diglycerides (DG). Additionally, an examination of lipid species reveals distinct profiles in each diagnostic group stratified by ε4 status, mainly in TG, saturated DG species and polyunsaturated phosphatidylserines. In summary, we show that peripheral lipids are promising biomarker candidates to assist with the differential diagnosis of mTBI and PTSD. Further, ε4 carrier status alone and in interaction with diagnosis has a strong influence on peripheral lipid levels. Therefore, examining ε4 status along with peripheral lipid levels could help with differential diagnosis of mTBI and PTSD.

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“…The application of advanced imaging modalities, such as functional MRI (fMRI) and diffusion-weighted imaging (DWI), has provided evidence of altered brain network connectivity after mTBI, although a clear-cut mechanism underlying continued symptoms has not been found [9,10]. There is also increasing evidence that certain protein biomarkers of cellular injury in the acute phase post-injury are informative of injury severity and clinical outcome after mTBI [11,12]. However, it is unclear if these markers have a role in the pathophysiology of persistent symptoms, and how this process may be influenced by other acute physiological sequelae such as inflammation or the acute stress response.…”

Section: Introductionmentioning

confidence: 99%

An integrated perspective linking physiological and psychological consequences of mild traumatic brain injury

et al. 2019

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Despite the often seemingly innocuous nature of a mild traumatic brain injury (mTBI), its consequences can be devastating, comprising debilitating symptoms that interfere with daily functioning. Currently, it is still difficult to pinpoint the exact cause of adverse outcome after mTBI. In fact, extensive research suggests that the underlying etiology is multifactorial. In the acute and early sub-acute stages, the pathophysiology of mTBI is likely to be dominated by complex physiological alterations including cellular injury, inflammation, and the acute stress response, which could lead to neural network dysfunction. In this stage, patients often report symptoms such as fatigue, headache, unstable mood and poor concentration. When time passes, psychological processes, such as coping styles, personality and emotion regulation, become increasingly influential. Disadvantageous, maladaptive, psychological mechanisms likely result in chronic stress which facilitates the development of long-lasting symptoms, possibly via persistent neural network dysfunction. So far, a systemic understanding of the coupling between these physiological and psychological factors that in concert define outcome after mTBI is lacking. The purpose of this narrative review article is to address how psychophysiological interactions may lead to poor outcome after mTBI. In addition, a framework is presented that may serve as a template for future studies on this subject.

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The current state of biomarkers of mild traumatic brain injury

Cited by 91 publications

References 104 publications

Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

An integrated perspective linking physiological and psychological consequences of mild traumatic brain injury

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